CA2188228C - Use of isoxazole and crotonamide derivatives for the treatment of carcinomatous disorders - Google Patents
Use of isoxazole and crotonamide derivatives for the treatment of carcinomatous disorders Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The compound of the formula I or II (see Formula II) is suitable for the production of a pharmaceutical for the treatment of carcinomatous disorders, where R1 is (C3-C5)-cycloalkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl, R2 is CF3 , OCF3, SCF3 , OH, NO2 , halogen, benzyl, phenyl, CN or O-phenyl, R3 is (C1-C4)-alkyl, halogen or a hydrogen atom and X is a -CH group or a nitrogen atom.
Description
HOECHST AKTIENGESELLSCHAFT HOE 95/ F247 Dr.TH/As The use of isoxazole and crotonamide derivatives for the treatment of carcinomatous disorders Description Chemotherapy is today available for the therapy of advanced hormone receptor-negative malignant tumors. Beside its limited efficiency, this form of therapy is characterized by the occurrence of often serious side effects. The active principle of the chemotherapeutics (inhibition of proliferation) must be regarded as a cause of the action and the side effects. Since, however, not only tumor cells, but also normal cells are in division, normal dividing cells in the body of the patient are inhibited from division just like the actual target cells, the tumor cells. The rapidly dividing cells of the hair follicles, of the gastrointestinal tract and of the bone marrow are particularly affected by the undesired side effects of the antiproliferative therapy.
The antiproliferative action of the chemotherapeutics is achieved, for example, by them intervening in the nucleic acid metabolism of the cell.
Particularly effective antiproliferative substances are the dihydroorotate dehydrogenase (DHODH) inhibitors. DHODH is a unique enzyme in the de novo synthesis of the pyrimidine nucleotides (Peters et al., 1990, Biochemical Pharmacology 39: No. 1, 135-144). The enzyme is concentrated on the outside of the inner mitochondrial membrane.
Inhibition of the enzyme by the active compound DUP-785 (Brequinar) leads to a depletion of pyrimidine ribo- and deoxyribonukleotides, but not of purine nucleotides (Schwartsmann et al., 1988, Biochem. Pharmacol.
37: 3257-3266). The depletion of dTTP and dCTP is proportional to that of UTP and CTP and can be prevented by the addition of uridine. The inhibition of growth exerted on in vitro cell lines by Brequinar can be abolished by addition of uridine or cytidine, but not by deoxythymidine or deoxycytidine. It can be concluded from this that the inhibition of UMP
The antiproliferative action of the chemotherapeutics is achieved, for example, by them intervening in the nucleic acid metabolism of the cell.
Particularly effective antiproliferative substances are the dihydroorotate dehydrogenase (DHODH) inhibitors. DHODH is a unique enzyme in the de novo synthesis of the pyrimidine nucleotides (Peters et al., 1990, Biochemical Pharmacology 39: No. 1, 135-144). The enzyme is concentrated on the outside of the inner mitochondrial membrane.
Inhibition of the enzyme by the active compound DUP-785 (Brequinar) leads to a depletion of pyrimidine ribo- and deoxyribonukleotides, but not of purine nucleotides (Schwartsmann et al., 1988, Biochem. Pharmacol.
37: 3257-3266). The depletion of dTTP and dCTP is proportional to that of UTP and CTP and can be prevented by the addition of uridine. The inhibition of growth exerted on in vitro cell lines by Brequinar can be abolished by addition of uridine or cytidine, but not by deoxythymidine or deoxycytidine. It can be concluded from this that the inhibition of UMP
synthesis is crucial for the proliferation-inhibiting effect on cell lines in vitro (Peters et al., 1987, Invest. New Drugs, 5: 235-244).
In the context of clinical investigations, it was possible to show that Brequinar significantly lowers the plasma uridine values (Peters et al., 1988, Proc. Am Ass. Cancer Res. 29: 350 (Abstract 1392)) (this finding is in agreement with the in vitro observations on various cell lines). In addition, the extent of effects on the in vivo uridine level correlated with the bone marrow and gastrointestinal tract toxicity (the side effects).
These clinical observations point to the fact that there is the urgent need to develop cancer therapeutics whose antitumor principle is not based on a general inhibition of proliferation, such as in the case of Brequinar, but on the inhibition of tumor-specific metabolic pathways.
It has now been found that the compounds of the formulae I and II only very weakly inhibit human DHODH, but very efficiently block very specific tumor cell lines in their division.
Addition of increasing amounts of uridine in the MTT test changes the IC50 value of the substances according to the invention on the LoVo cell line only insignificantly, completely in contrast to the massive increase in the IC50 value of Brequinar on the same cell line (Example 7).
These experimental findings support the assumption that the antiproliferative action of the substances according to the invention is based on a principle of action other than an inhibition of DHODH as in the case of Brequinar.
It was possible to show by means of fluorescence microscopy techniques that those cell lines which strongly overexpress the PDGF receptor and the VEGF receptor are also efficiently prevented from division (Example 6) by very low concentrations of the substances according to the invention (lower IC50). This observation as a result points to the fact that the substances according to the invention could block specific receptor tyrosine kinases, such as, for example, the PDGF receptor, i.e.
advantageously affect the abnormal signal transmission in tumor cells.
The invention therefore relates to the use of a compound of the formula I
or II
O
H I I
CN R 2 (~) X-N,0 O R R3 O
ii 2 NC-C- CNH R
X-HO~ R, and/or an optionally stereoisomeric form of the compound of the formula I or II and/or a physiologically tolerable salt of the compound of the formula II for the production of a pharmaceutical for the treatment of carcinomatous disorders, where R' is a) (C3-C5)-cycloalkyl, b) (C2-C6)-alkenyl or c) (C2 CO-alkynyl, R2 is a) -CF3 , b) -O-CF3, c) -S-CF31 d) -OH, e) -NO29 t) halogen, g) benzyl, h) phenyl, i) -CN, k) -0-phenyl, I) -0-phenyl, mono- or polysubstituted by 1) (Cl-C4)-alkyl, 2) halogen, 3) -0-CF3 or 4) -O-CH31 R3 is a) (Cl-C4)-alkyl, b) halogen or c) a hydrogen atom, and X is a) a -CH group or b) a nitrogen atom.
The use is preferred of a compound of the formula I or II and/or an optionally stereoisomeric form of the compound of the formula I or II
and/or sodium or lysinium salts of the compound of the formula II, where R1 is cyclopropyl, (C2-C3)-alkenyl or (C3-C5)-alkynyl, R2 is -0-CF3, -S-CF3, -0-phenyl, phenyl, -CF3, -CN or -0-phenyl, mono- or polysubstituted by (Cl-C4)-alkyl or halogen, R3 is a hydrogen atom or methyl, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
The use is particularly preferred of a compound of the formula I or II, where R' is cyclopropyl, C3-alkenyl or C4-alkynyl, R2 is -S-CF3, CN, 2-methyl-4-chlorophenyl or CF3, 5 R3 is a hydrogen atom, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
In particular, the use is preferred of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxyhexa-2,5-dienecarboxamide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-trifluoromethylphenyl)amide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-thiotrifluoromethylphenyl)amide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (2-methyl-4-chlorophenyl)amide, N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-hept-2-en-6-ynecarboxamide lysine or sodium salt or 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide lysine or sodium salt.
The compounds of the formula I or II are prepared by known processes such as are described in EP 13 376; EP 484 223; EP 538 783; EP 551 230 or US 4 061 767.
The term alkyl, alkenyl or alkynyl is understood as meaning radicals whose carbon chain can be straight-chain or branched. The alkenyl or alkynyl radicals can furthermore also contain two or more double bonds or two or more triple bonds. Cyclic alkyl radicals are, for example, 3- to 5-membered monocyclic systems such as cyclopropyl, cyclobutyl or cyclopentyl. The starting substances for the chemical reactions are known or can be readily prepared by methods known from the literature.
The carcinomatous disorders include, for example, leukemia, in particular chronic leukemia of the T- and B-cell type, Hodgkin's or non-Hodgkin's lymphoma, carcinoma, lung cancer, ovarian cancer, lymph node cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, brain tumors, breast cancer, stomach cancer, pancreatic cancer, prostatic cancer or skin cancer.
The invention also relates to a process for the production of a pharmaceutical for the treatment of carcinomatous disorders, which comprises bringing the compound of the formula I or II and/or a physiologically tolerable salt of the compound of the formula II into a suitable administration form using a pharmaceutically suitable and physiologically acceptable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries. The pharmaceuticals according to the invention can be administered orally, topically, rectally, intravenously or alternatively parenterally.
Suitable solid or liquid pharmaceutical administration forms are, for example, granules, powders, coated tablets, tablets, (micro)capsuies, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and also preparations having a protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners or solubilizers are used.
Frequently used auxiliaries which may be mentioned are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as, for example, sterile water and mono- or polyhydric alcohols, e.g. glycerol.
Preferably, the pharmaceutical preparations are prepared and administered in dose units, each unit as active constituent containing a certain dose of the compound of the formula I or II and/or physiologically tolerable salts of the compound of the formula II. In the case of solid dose units, such as tablets, capsules or suppositories, this dose can be up to approximately 300 mg, but preferably 10 to 200 mg.
In the context of clinical investigations, it was possible to show that Brequinar significantly lowers the plasma uridine values (Peters et al., 1988, Proc. Am Ass. Cancer Res. 29: 350 (Abstract 1392)) (this finding is in agreement with the in vitro observations on various cell lines). In addition, the extent of effects on the in vivo uridine level correlated with the bone marrow and gastrointestinal tract toxicity (the side effects).
These clinical observations point to the fact that there is the urgent need to develop cancer therapeutics whose antitumor principle is not based on a general inhibition of proliferation, such as in the case of Brequinar, but on the inhibition of tumor-specific metabolic pathways.
It has now been found that the compounds of the formulae I and II only very weakly inhibit human DHODH, but very efficiently block very specific tumor cell lines in their division.
Addition of increasing amounts of uridine in the MTT test changes the IC50 value of the substances according to the invention on the LoVo cell line only insignificantly, completely in contrast to the massive increase in the IC50 value of Brequinar on the same cell line (Example 7).
These experimental findings support the assumption that the antiproliferative action of the substances according to the invention is based on a principle of action other than an inhibition of DHODH as in the case of Brequinar.
It was possible to show by means of fluorescence microscopy techniques that those cell lines which strongly overexpress the PDGF receptor and the VEGF receptor are also efficiently prevented from division (Example 6) by very low concentrations of the substances according to the invention (lower IC50). This observation as a result points to the fact that the substances according to the invention could block specific receptor tyrosine kinases, such as, for example, the PDGF receptor, i.e.
advantageously affect the abnormal signal transmission in tumor cells.
The invention therefore relates to the use of a compound of the formula I
or II
O
H I I
CN R 2 (~) X-N,0 O R R3 O
ii 2 NC-C- CNH R
X-HO~ R, and/or an optionally stereoisomeric form of the compound of the formula I or II and/or a physiologically tolerable salt of the compound of the formula II for the production of a pharmaceutical for the treatment of carcinomatous disorders, where R' is a) (C3-C5)-cycloalkyl, b) (C2-C6)-alkenyl or c) (C2 CO-alkynyl, R2 is a) -CF3 , b) -O-CF3, c) -S-CF31 d) -OH, e) -NO29 t) halogen, g) benzyl, h) phenyl, i) -CN, k) -0-phenyl, I) -0-phenyl, mono- or polysubstituted by 1) (Cl-C4)-alkyl, 2) halogen, 3) -0-CF3 or 4) -O-CH31 R3 is a) (Cl-C4)-alkyl, b) halogen or c) a hydrogen atom, and X is a) a -CH group or b) a nitrogen atom.
The use is preferred of a compound of the formula I or II and/or an optionally stereoisomeric form of the compound of the formula I or II
and/or sodium or lysinium salts of the compound of the formula II, where R1 is cyclopropyl, (C2-C3)-alkenyl or (C3-C5)-alkynyl, R2 is -0-CF3, -S-CF3, -0-phenyl, phenyl, -CF3, -CN or -0-phenyl, mono- or polysubstituted by (Cl-C4)-alkyl or halogen, R3 is a hydrogen atom or methyl, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
The use is particularly preferred of a compound of the formula I or II, where R' is cyclopropyl, C3-alkenyl or C4-alkynyl, R2 is -S-CF3, CN, 2-methyl-4-chlorophenyl or CF3, 5 R3 is a hydrogen atom, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
In particular, the use is preferred of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxyhexa-2,5-dienecarboxamide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-trifluoromethylphenyl)amide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-thiotrifluoromethylphenyl)amide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (2-methyl-4-chlorophenyl)amide, N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-hept-2-en-6-ynecarboxamide lysine or sodium salt or 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide lysine or sodium salt.
The compounds of the formula I or II are prepared by known processes such as are described in EP 13 376; EP 484 223; EP 538 783; EP 551 230 or US 4 061 767.
The term alkyl, alkenyl or alkynyl is understood as meaning radicals whose carbon chain can be straight-chain or branched. The alkenyl or alkynyl radicals can furthermore also contain two or more double bonds or two or more triple bonds. Cyclic alkyl radicals are, for example, 3- to 5-membered monocyclic systems such as cyclopropyl, cyclobutyl or cyclopentyl. The starting substances for the chemical reactions are known or can be readily prepared by methods known from the literature.
The carcinomatous disorders include, for example, leukemia, in particular chronic leukemia of the T- and B-cell type, Hodgkin's or non-Hodgkin's lymphoma, carcinoma, lung cancer, ovarian cancer, lymph node cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, brain tumors, breast cancer, stomach cancer, pancreatic cancer, prostatic cancer or skin cancer.
The invention also relates to a process for the production of a pharmaceutical for the treatment of carcinomatous disorders, which comprises bringing the compound of the formula I or II and/or a physiologically tolerable salt of the compound of the formula II into a suitable administration form using a pharmaceutically suitable and physiologically acceptable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries. The pharmaceuticals according to the invention can be administered orally, topically, rectally, intravenously or alternatively parenterally.
Suitable solid or liquid pharmaceutical administration forms are, for example, granules, powders, coated tablets, tablets, (micro)capsuies, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and also preparations having a protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners or solubilizers are used.
Frequently used auxiliaries which may be mentioned are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as, for example, sterile water and mono- or polyhydric alcohols, e.g. glycerol.
Preferably, the pharmaceutical preparations are prepared and administered in dose units, each unit as active constituent containing a certain dose of the compound of the formula I or II and/or physiologically tolerable salts of the compound of the formula II. In the case of solid dose units, such as tablets, capsules or suppositories, this dose can be up to approximately 300 mg, but preferably 10 to 200 mg.
For the treatment of a patient (70 kg), in early phases an intravenous infusion treatment of at most 1200 mg per day and in the later rehabilitation phase an oral administration of 3 times 300 mg per day of the compound of the formula I or II and/or of the corresponding salts of the compound of the formula II are indicated.
Under certain circumstances, however, even higher or lower doses may be appropriate. The dose can be administered both by single administration in the form of an individual dose unit or else of several smaller dose units and by multiple administration of subdivided doses at certain intervals.
Finally, the compounds of the formula I or II and/or their corresponding salts can also be combined together with other suitable active compounds, for example antiuricopathics, platelet aggregation inhibitors, analgesics and steroidal or nonsteroidal antiinflammatories, during the preparation of the abovementioned pharmaceutical administration forms.
Under certain circumstances, however, even higher or lower doses may be appropriate. The dose can be administered both by single administration in the form of an individual dose unit or else of several smaller dose units and by multiple administration of subdivided doses at certain intervals.
Finally, the compounds of the formula I or II and/or their corresponding salts can also be combined together with other suitable active compounds, for example antiuricopathics, platelet aggregation inhibitors, analgesics and steroidal or nonsteroidal antiinflammatories, during the preparation of the abovementioned pharmaceutical administration forms.
Example 1 N-(4-Trifluoromethylphenyl)-2-cya no-3-hyd roxyhept-2-en-6-yne-carboxamide sodium salt (compound 1) 50 g (0.15 mol) of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxyhept-2-en-6-ynecarboxamide are dissolved in a two-phase system of 50 ml of 5 N sodium hydroxide solution and 500 ml of ethyl acetate, and the organic phase is separated off, washed twice with a little water, dried over sodium sulfate and concentrated. The oily residue is taken up using 500 ml of tertiary-butyl methyl ether and stirred at room temperature for 4 hours (h) to complete crystallization, filtered and dried under reduced pressure. For the complete removal of solvent residues, the crystalline product is suspended under reflux for 10 min in 500 ml of toluene, cooled with stirring, filtered off with suction again and dried under reduced pressure. Yield: 41.1 g (77%) of melting point >244 C decomposition (dec.).
C15H1oF3N2O2Na (330.24 g/mol):
calculated C: 54.0 H: 3.5 N:8.4 Na: 6.88 (calc. for 1.1 % water) found C: 54.4 H: 3.4 N:8.4 Na: 6.65 water: 1.1%
Example 2 2-Cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide sodium salt (compound 2) 15 g (0.059 mol) of 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide are suspended in 120 ml of water and 100 ml of acetone and brought into solution by addition of 60 ml of 1 N NaOH. After filtration of traces of undissolved material, the solution is concentrated under reduced pressure in a rotary evaporator to approximately 200 ml, and the product is crystallized overnight at 0 C, filtered off with suction and dried under reduced pressure.
Yield: 13 g, m.p. >280 C.
C14H1oN3O2Na (275.24):
C15H1oF3N2O2Na (330.24 g/mol):
calculated C: 54.0 H: 3.5 N:8.4 Na: 6.88 (calc. for 1.1 % water) found C: 54.4 H: 3.4 N:8.4 Na: 6.65 water: 1.1%
Example 2 2-Cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide sodium salt (compound 2) 15 g (0.059 mol) of 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide are suspended in 120 ml of water and 100 ml of acetone and brought into solution by addition of 60 ml of 1 N NaOH. After filtration of traces of undissolved material, the solution is concentrated under reduced pressure in a rotary evaporator to approximately 200 ml, and the product is crystallized overnight at 0 C, filtered off with suction and dried under reduced pressure.
Yield: 13 g, m.p. >280 C.
C14H1oN3O2Na (275.24):
calculated C: 60.7 H: 3.7 N:15.2 (calc. for 0.7% water) found C:60.8 H: 3.6 N:15.3 water: 0.7%
Example 3 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxyhept-2-en-6-yne-carboxamide lysine salt 30 g (0.097 mol) of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-hept-2-en-6-ynecarboxamide are dissolved in 1 I of water and 25 ml of ethanol together with 17.3 g (0.097 mol) of L-lysine hydrate, filtered and lyophilized. Adhering residual amounts of ethanol are removed by repeated freeze drying.
Yield: 44.4 g of mainly amorphous product, m.p. 135-138 C.
1H-NMR (DMSO-d6): 1.23-1.77 (m, 6H), 2.3-2.45 (m, 2H), 2.50-2.65 (m, 2H), 2.7-2.85 (m, 3H), 3.25 (tb, 1 H), 5.7-7.4 (sb, 6H), 7.55 and 7.73 (AA'BB', in each case 2H), 12.35 (s, 1 H) Example 4 2-Cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide lysine salt 15 g (0.054 mol) of 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide are dissolved in 900 ml of water and 10 ml of ethanol together with 9.6 g (0.054 mol) of L-lysine hydrate, filtered and lyophilized. Adhering residual amounts of ethanol are removed by drying under reduced pressure.
Yield: 21.8 g of mainly amorphous product, m.p.>100 C (dec.).
1 H-NMR (DMSO-d6): 0.6-0.82 (m, 4H), 1.27-1.75 (m, 6H), 2.17 (mc, 1 H), 2.77 (tb, 2H), 3.28 (tb, 1 H), 4.8-7.5 (sb, 6H), 7.63 and 7.7 (AA'BB', in each case 2H), 12.6 (s, 1 H) Example 5 Human DHODH (spleen) enzyme activity is determined according to Williamson et al. (The Journal of Biological Chemistry, 270, (1995), pages 22467-22472). The IC50 value is in each case given in nM.
Table 1:
DHODH
IC50 in nM
Compound 1 292 10 Compound 2 625 Compound 12 539 Brequinar 4 Example 6 Inhibition of the proliferation of tumor cells (MTT test) 1 x 104 cells per well are inoculated into a 96-well microtiter plate. After h, the test substances are added at various concentrations. Each group consists of 4 wells, th~ :ontrol is only incubated with medium. After 65 h, 50 NI of MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; 2.5 mg/mI in PBS) are added and, after 7 h, the supernatant is removed. The color formed by the living cells is dissolved by addition of 100 NI of dimethyl sulfoxide/well. The extinction is measured at 492 nm for each well with the aid of a Multiscan photometer 340 CC (Flow). The cell lines used are obtainable as follows from the American Type Culture Collection:
HUV-EC-C is ATCC CRL 1730; A-172 is ATCC CRL 1620; L 1210 is ATCC
CCL 219; LoVo is ATCC CCL 229; C 6 is ATCC CCL 107 and a rat glioblastoma cell line.
The mean value is formed from the 4 wells of a group and the IC50 values are calculated from the dose-response curve using the Software 3.0 (Erithacus Software Ltd.). Table 2 shows the results.
Example 3 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxyhept-2-en-6-yne-carboxamide lysine salt 30 g (0.097 mol) of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-hept-2-en-6-ynecarboxamide are dissolved in 1 I of water and 25 ml of ethanol together with 17.3 g (0.097 mol) of L-lysine hydrate, filtered and lyophilized. Adhering residual amounts of ethanol are removed by repeated freeze drying.
Yield: 44.4 g of mainly amorphous product, m.p. 135-138 C.
1H-NMR (DMSO-d6): 1.23-1.77 (m, 6H), 2.3-2.45 (m, 2H), 2.50-2.65 (m, 2H), 2.7-2.85 (m, 3H), 3.25 (tb, 1 H), 5.7-7.4 (sb, 6H), 7.55 and 7.73 (AA'BB', in each case 2H), 12.35 (s, 1 H) Example 4 2-Cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide lysine salt 15 g (0.054 mol) of 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide are dissolved in 900 ml of water and 10 ml of ethanol together with 9.6 g (0.054 mol) of L-lysine hydrate, filtered and lyophilized. Adhering residual amounts of ethanol are removed by drying under reduced pressure.
Yield: 21.8 g of mainly amorphous product, m.p.>100 C (dec.).
1 H-NMR (DMSO-d6): 0.6-0.82 (m, 4H), 1.27-1.75 (m, 6H), 2.17 (mc, 1 H), 2.77 (tb, 2H), 3.28 (tb, 1 H), 4.8-7.5 (sb, 6H), 7.63 and 7.7 (AA'BB', in each case 2H), 12.6 (s, 1 H) Example 5 Human DHODH (spleen) enzyme activity is determined according to Williamson et al. (The Journal of Biological Chemistry, 270, (1995), pages 22467-22472). The IC50 value is in each case given in nM.
Table 1:
DHODH
IC50 in nM
Compound 1 292 10 Compound 2 625 Compound 12 539 Brequinar 4 Example 6 Inhibition of the proliferation of tumor cells (MTT test) 1 x 104 cells per well are inoculated into a 96-well microtiter plate. After h, the test substances are added at various concentrations. Each group consists of 4 wells, th~ :ontrol is only incubated with medium. After 65 h, 50 NI of MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; 2.5 mg/mI in PBS) are added and, after 7 h, the supernatant is removed. The color formed by the living cells is dissolved by addition of 100 NI of dimethyl sulfoxide/well. The extinction is measured at 492 nm for each well with the aid of a Multiscan photometer 340 CC (Flow). The cell lines used are obtainable as follows from the American Type Culture Collection:
HUV-EC-C is ATCC CRL 1730; A-172 is ATCC CRL 1620; L 1210 is ATCC
CCL 219; LoVo is ATCC CCL 229; C 6 is ATCC CCL 107 and a rat glioblastoma cell line.
The mean value is formed from the 4 wells of a group and the IC50 values are calculated from the dose-response curve using the Software 3.0 (Erithacus Software Ltd.). Table 2 shows the results.
Table 2:
MTT Test IC50 in pM
Cell Origin (human) Compound Compound Brequinar LoVo Colonic carcinoma 137 392 0.388 HUV-EC-C Endothelial cell 164 360 9.4 A-172 Glioblastoma 78 169 0.2 L1210 Leukemia (mouse) 9.1 6.1 1.0 C 6 Rat glioblastoma 68 20 9 Example 7 The procedure is as in Example 6; uridine is additionally added to the batches. Table 3 shows the results.
Table 3:
MTT Test on LoVo cells IC50 in pM
Uridine [pM] Compound 1 Compound 2 Brequinar 0 168.0 359.2 0.388 1000 277.7 560.0 128.8 The compounds mentioned in Table 4 are prepared as in Examples 1 to 4.
The compounds are tested as described in Example 6.
MTT Test IC50 in pM
Cell Origin (human) Compound Compound Brequinar LoVo Colonic carcinoma 137 392 0.388 HUV-EC-C Endothelial cell 164 360 9.4 A-172 Glioblastoma 78 169 0.2 L1210 Leukemia (mouse) 9.1 6.1 1.0 C 6 Rat glioblastoma 68 20 9 Example 7 The procedure is as in Example 6; uridine is additionally added to the batches. Table 3 shows the results.
Table 3:
MTT Test on LoVo cells IC50 in pM
Uridine [pM] Compound 1 Compound 2 Brequinar 0 168.0 359.2 0.388 1000 277.7 560.0 128.8 The compounds mentioned in Table 4 are prepared as in Examples 1 to 4.
The compounds are tested as described in Example 6.
Com- Structure A172 C 6 LoVo HUVE
pound C
N
1 ~ 78 68 137 164 HC N
O O
Na* F
N
-NaO 0 N
N
F
F
5 F ~ O O H 30 5 34 94 N
II
N
CI
OH
6 25 11 24 >400 N
II
N
Br O O H
N
II
N
N ~
I I
N
F F
g F ~ H 193 21 400 >400 N
pound C
N
1 ~ 78 68 137 164 HC N
O O
Na* F
N
-NaO 0 N
N
F
F
5 F ~ O O H 30 5 34 94 N
II
N
CI
OH
6 25 11 24 >400 N
II
N
Br O O H
N
II
N
N ~
I I
N
F F
g F ~ H 193 21 400 >400 N
Com- Structure A172 C 6 LoVo HUVE
pound C
F+ F
N
F
F ~
/ N CH=
N
F
12 F F / CH~
N
N
13 F OH 32 13 15 >400 N
~\ O
N F
O F
Na F $
N ~
II
N
16 cl--- 0 H 17 36 7 299 CI' CH3 N
N
pound C
F+ F
N
F
F ~
/ N CH=
N
F
12 F F / CH~
N
N
13 F OH 32 13 15 >400 N
~\ O
N F
O F
Na F $
N ~
II
N
16 cl--- 0 H 17 36 7 299 CI' CH3 N
N
Com- Structure A172 C 6 LoVo HUVE
pound C
il H
OH O
F
F
II
I /
F s 19 F F I o Ho 118 32 171 135 il N
~ ~ ~ ~ 0 OH
20 F ~ N 158 182 119 >400 N
~
OH O
CI
O OH
>400 103 149 >400 Jj' 'CH2 N
F HO
~~
23 FN " 94 7 75 >400 F _ O
N
Com- Structure A172 C 6 LoVo HUVE
pound C
HO
O
H+C N
OH O F
F
F
N
27 142 126 153 >400 N
HC/~
OH O NI
CI
pound C
il H
OH O
F
F
II
I /
F s 19 F F I o Ho 118 32 171 135 il N
~ ~ ~ ~ 0 OH
20 F ~ N 158 182 119 >400 N
~
OH O
CI
O OH
>400 103 149 >400 Jj' 'CH2 N
F HO
~~
23 FN " 94 7 75 >400 F _ O
N
Com- Structure A172 C 6 LoVo HUVE
pound C
HO
O
H+C N
OH O F
F
F
N
27 142 126 153 >400 N
HC/~
OH O NI
CI
Claims (5)
1. A use of a sodium or lysinium salt of the compound of the formula II
and/or an optionally stereoisomeric form of the sodium or lysinium salt of the compound of the formula II for the production of a pharmaceutical for the treatment of carcinomatous disorders, where R1 is a) (C3-C5)-cycloalkyl, R2 is a) -CF3, b) -O-CF3, c) -S-CF3, d) -OH, e) -NO2, f) halogen, g) benzyl, h) phenyl, i) -CN, k) -O-phenyl or l) -O-phenyl, mono- or polysubstituted by 1) (C1-C4)-alkyl,
and/or an optionally stereoisomeric form of the sodium or lysinium salt of the compound of the formula II for the production of a pharmaceutical for the treatment of carcinomatous disorders, where R1 is a) (C3-C5)-cycloalkyl, R2 is a) -CF3, b) -O-CF3, c) -S-CF3, d) -OH, e) -NO2, f) halogen, g) benzyl, h) phenyl, i) -CN, k) -O-phenyl or l) -O-phenyl, mono- or polysubstituted by 1) (C1-C4)-alkyl,
2) halogen,
3) -O-CF3 or
4) -O-CH3, R3 is a) (C1-C4)-alkyl, b) halogen or c) a hydrogen atom, and X is a) a -CH group or b) a nitrogen atom.
2. The use of the sodium or lysinium salts of the compound of the formula II
as claimed in claim 1, where R1 is a) cyclopropyl, R2 is a) -CF3 b) -O-CF3, c) -S-CF3, d) -O-phenyl, e) -phenyl, f) -CN or g) -O-phenyl, mono- or polysubstituted by (C1-C4)-alkyl or halogen, R3 is a hydrogen atom or methyl, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
3. The use of the sodium or lysinium salts of the compound of the formula II
as claimed in claim 1 or 2, where R1 is cyclopropyl, R2 is -S-CF3, CN, or CF3, R3 is a hydrogen atom, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
4. The use of the compound of the formula II as claimed in any one of claims 1 to 3, wherein the sodium or lysinium salt of 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-trifluoromethylphenyl)amide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-thiotrifluoromethyl-phenyl)amide or 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide is employed.
2. The use of the sodium or lysinium salts of the compound of the formula II
as claimed in claim 1, where R1 is a) cyclopropyl, R2 is a) -CF3 b) -O-CF3, c) -S-CF3, d) -O-phenyl, e) -phenyl, f) -CN or g) -O-phenyl, mono- or polysubstituted by (C1-C4)-alkyl or halogen, R3 is a hydrogen atom or methyl, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
3. The use of the sodium or lysinium salts of the compound of the formula II
as claimed in claim 1 or 2, where R1 is cyclopropyl, R2 is -S-CF3, CN, or CF3, R3 is a hydrogen atom, and X is a -CH group, for the production of a pharmaceutical for the treatment of carcinomatous disorders.
4. The use of the compound of the formula II as claimed in any one of claims 1 to 3, wherein the sodium or lysinium salt of 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-trifluoromethylphenyl)amide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-thiotrifluoromethyl-phenyl)amide or 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide is employed.
5. The use of the sodium or lysinium salts of the compound of the formula II
and/or an optionally steroisomeric form of the sodium or lysinium salts of the compound of the formula II as claimed in claim 1, for the production of a pharmaceutical for the treatment of leukemia, chronic leukemia of the T-or B-cell type, Hodgkin's or non-Hodgkin's lymphoma, carcinoma, lung cancer, ovarian cancer, lymph node cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, brain tumors, breast cancer, stomach cancer, pancreatic cancer, prostatic cancer or skin cancer.
and/or an optionally steroisomeric form of the sodium or lysinium salts of the compound of the formula II as claimed in claim 1, for the production of a pharmaceutical for the treatment of leukemia, chronic leukemia of the T-or B-cell type, Hodgkin's or non-Hodgkin's lymphoma, carcinoma, lung cancer, ovarian cancer, lymph node cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, brain tumors, breast cancer, stomach cancer, pancreatic cancer, prostatic cancer or skin cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19539638.3 | 1995-10-25 | ||
| DE19539638A DE19539638A1 (en) | 1995-10-25 | 1995-10-25 | The use of isoxazole and crotonic acid amide derivatives for the treatment of cancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2188228A1 CA2188228A1 (en) | 1997-04-26 |
| CA2188228C true CA2188228C (en) | 2008-08-12 |
Family
ID=7775689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002188228A Expired - Fee Related CA2188228C (en) | 1995-10-25 | 1996-10-18 | Use of isoxazole and crotonamide derivatives for the treatment of carcinomatous disorders |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US5886033A (en) |
| EP (1) | EP0769296B1 (en) |
| JP (1) | JP3996658B2 (en) |
| AT (1) | ATE202704T1 (en) |
| CA (1) | CA2188228C (en) |
| DE (2) | DE19539638A1 (en) |
| DK (1) | DK0769296T3 (en) |
| ES (1) | ES2160197T3 (en) |
| GR (1) | GR3036754T3 (en) |
| PT (1) | PT769296E (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2302438A1 (en) * | 1997-05-19 | 1998-11-26 | Sugen, Inc. | Heteroarylcarboxamide compounds active against protein tyrosine kinase related disorders |
| US6316479B1 (en) | 1997-05-19 | 2001-11-13 | Sugen, Inc. | Isoxazole-4-carboxamide compounds active against protein tryosine kinase related disorders |
| PT903345E (en) * | 1997-08-08 | 2001-01-31 | Aventis Pharma Gmbh | CRYSTALLINE FORM OF N- (4-TRIFLUOROMETHYLPHENYL) -5-METHYL ISOXAZOLE-4-CARBOXAMIDE |
| EP0933633A1 (en) * | 1997-12-11 | 1999-08-04 | Hoechst Marion Roussel Deutschland GmbH | Process for obtaining L-dihydroorotic acid and use thereof |
| DE19857009A1 (en) * | 1998-12-10 | 2000-06-15 | Aventis Pharma Gmbh | Preparation with improved therapeutic range, containing nucleotide synthesis inhibitors |
| US7247736B2 (en) * | 2002-12-23 | 2007-07-24 | 4Sc Ag | Method of identifying inhibitors of DHODH |
| US7365094B2 (en) | 2002-12-23 | 2008-04-29 | 4Sc Ag | Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
| US7071355B2 (en) | 2002-12-23 | 2006-07-04 | 4 Sc Ag | Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
| US7842815B2 (en) | 2004-06-17 | 2010-11-30 | Infinity Pharmaceuticals, Inc. | Compounds and methods for inhibiting the interaction of BCL proteins with binding partners |
| WO2006009869A1 (en) | 2004-06-17 | 2006-01-26 | Infinity Pharmaceuticals, Inc. | Coumpounds and methods for inhibiting the interaction of bcl proteins with binding partners |
| DE102006014165A1 (en) * | 2006-03-24 | 2007-09-27 | Schebo Biotech Ag | New isooxazol derivative useful in the preparation of pharmaceutical composition for the treatment of disease associated with cellular metabolic derailment e.g. lung cancer, leukemia, ovarian cancer, sarcoma and meningioma |
| TWI389895B (en) | 2006-08-21 | 2013-03-21 | Infinity Discovery Inc | Compounds and methods for inhibiting the interaction of bcl proteins with binding partners |
| CN114288294A (en) * | 2015-09-01 | 2022-04-08 | 布罗德研究所股份有限公司 | Compounds and methods for treating or preventing hematologic cancers |
| CN111423374B (en) * | 2020-05-18 | 2023-03-21 | 合肥工业大学 | Dihydropyrazole sulfonamide compound and preparation method and application thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL186239B (en) * | 1975-06-05 | Hoechst Ag | PROCESS FOR THE PREPARATION OF A MEDICINAL PRODUCT WITH ANTIFLOGISTICAL AND / OR ANALGETICAL ACTION AND PROCEDURE FOR THE PREPARATION OF A 2-HYDROXYETHYLIDE ENCYANAACETIC ANILIDE SUITABLE FOR USE IN THIS PROCESS. | |
| DE2854439A1 (en) * | 1978-12-16 | 1980-07-03 | Hoechst Ag | AN ISOXAZOLE DERIVATIVE, METHOD FOR THE PRODUCTION THEREOF, AGENT AND USE THEREOF |
| EP0527736B1 (en) * | 1990-05-18 | 1997-04-16 | Hoechst Aktiengesellschaft | Isoxazole-4-carboxamides and hydroxyalkylidene-cyanoacetamides, drugs containing these compounds and use of such drugs |
| IL99811A (en) * | 1990-10-30 | 1996-03-31 | Roussel Uclaf | 3-cycloalkyl-propanamides their tautomer forms and their salts preparation process and compositions containing them |
| DK0538783T3 (en) * | 1991-10-23 | 1996-02-05 | Hoechst Ag | N-Phenyl-2-cyano-3-hydroxycrotonic acid derivatives and their use in drugs with immunomodulatory properties |
| GB9200275D0 (en) * | 1992-01-08 | 1992-02-26 | Roussel Lab Ltd | Chemical compounds |
| GB9320299D0 (en) * | 1993-10-01 | 1993-11-17 | Roussel Lab Ltd | Isoxazole derivatives |
| US5700823A (en) * | 1994-01-07 | 1997-12-23 | Sugen, Inc. | Treatment of platelet derived growth factor related disorders such as cancers |
| US5519042A (en) * | 1994-01-13 | 1996-05-21 | Hoechst Aktiengesellschaft | Method of treating hyperproliferative vascular disease |
-
1995
- 1995-10-25 DE DE19539638A patent/DE19539638A1/en not_active Withdrawn
-
1996
- 1996-10-14 EP EP96116408A patent/EP0769296B1/en not_active Expired - Lifetime
- 1996-10-14 AT AT96116408T patent/ATE202704T1/en active
- 1996-10-14 ES ES96116408T patent/ES2160197T3/en not_active Expired - Lifetime
- 1996-10-14 PT PT96116408T patent/PT769296E/en unknown
- 1996-10-14 DE DE59607208T patent/DE59607208D1/en not_active Expired - Lifetime
- 1996-10-14 DK DK96116408T patent/DK0769296T3/en active
- 1996-10-16 US US08/733,050 patent/US5886033A/en not_active Expired - Lifetime
- 1996-10-18 CA CA002188228A patent/CA2188228C/en not_active Expired - Fee Related
- 1996-10-24 JP JP28191896A patent/JP3996658B2/en not_active Expired - Fee Related
-
1998
- 1998-11-13 US US09/191,375 patent/US6020372A/en not_active Expired - Lifetime
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2001
- 2001-09-28 GR GR20010401611T patent/GR3036754T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0769296B1 (en) | 2001-07-04 |
| JP3996658B2 (en) | 2007-10-24 |
| EP0769296A1 (en) | 1997-04-23 |
| ES2160197T3 (en) | 2001-11-01 |
| DK0769296T3 (en) | 2001-10-22 |
| US6020372A (en) | 2000-02-01 |
| DE59607208D1 (en) | 2001-08-09 |
| PT769296E (en) | 2001-11-30 |
| JPH09165336A (en) | 1997-06-24 |
| CA2188228A1 (en) | 1997-04-26 |
| ATE202704T1 (en) | 2001-07-15 |
| GR3036754T3 (en) | 2001-12-31 |
| US5886033A (en) | 1999-03-23 |
| DE19539638A1 (en) | 1997-04-30 |
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